ABSTRACT Orthodontic treatment need has been assessed on the basis of complete orthodontic records in a random sample of 293 Danish children aged 13–17 years by a group of postgraduate orthodontic ...students and by three orthodontists. The estimates of treatment need ranged from 45 % to 61 %. Interexaminer agreement in pairs was observed in 77 %– 92 % (mean 83 %) of the cases. Uniformity in four individual assessments was reached in 69 % of the cases: 38 % were considered in need of treatment and 31 % were considered not to present such need; conversely, 31 % gave rise to disagreement. It is argued that, at present, the orthodontist's subjective estimate of treatment need probably constitutes a more realistic approach to the problem of assigning treatment priority than the various indices of malocclusion.
The behaviour of rats was studied after combined treatment with the selective DA D-2 agonist quinpirole and three selective D-1 agonists (SK & F 38393, SK & F 75670 and Lu 24-040). The effects on ...behaviour were compared with those on receptor binding and adenylate cyclase (AC). While the D-1 agonists alone did not induce stereotyped behaviour, quinpirole induced dose-dependent hyperactivity (locomotion, sniffing, head movements and rearing), whereas licking/biting was absent or seen only occasionally. Combined treatment with quinpirole and a D-1 agonist was followed by dose-dependent licking and occasional biting behaviour. The D-1 agonists had similar efficacies, but SK & F 75670 and Lu 24-040 were more potent than SK & F 38393. The maximal effects of SK & F 38393 plus quinpirole were effectively blocked by either a D-1 antagonist (SCH 23390) or a D-2 antagonist (YM 09151-2) confirming the close relation between D-1 and D-2 receptor sites in the brain. Good correspondence was found between affinities to D-1 receptors ( 3HSCH 23390 binding) in vitro and the EC50 values for stimulation of AC activity. However, the maximal effects on DA-sensitive AC activity were less for SK & F 75670 and Lu 24-040 than for SK & F 38393. Thus, the results indicate that efficacies in the adenylate cyclase assay are dissociated from those on behaviour. Furthermore, the data indicate that in normal rats D-1 receptors are functionally relevant since D-1 agonists facilitate the expression of oral stereotyped behaviour after combination with a D-2 agonist.
A series of 1-(4-fluorophenyl)-1H-indoles substituted at the 3-position with 1-piperazinyl, 1,2,3,6-tetrahydro-4-pyridinyl, and 4-piperidinyl was synthesized. Within all three subseries potent ...dopamine D-2 and serotonin 5-HT2 receptor affinity was found in ligand binding studies. Quipazine-induced head twitches in rats were inhibited by most derivatives as a measure of central 5-HT2 receptor antagonism. Piperazinyl and tetrahydropyridyl indoles were cataleptogenic, while piperidyl substituted indoles surprisingly were found to be noncataleptogenic or only weakly cataleptogenic. Noncataleptogenic piperidyl derivatives also failed to block dopaminergic-mediated stereotypies, that is methyl phenidate-induced gnawing behavior in mice. These profiles resemble that of the atypical neuroleptic clozapine. 1-Ethyl-2-imidazolidinone was found to be the optimal substituent of the basic nitrogen atom in order to avoid catalepsy. The atypical neuroleptic 1-2-4-5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl-1-piperidinyl ethyl-2-imidazolidinone (sertindole, compound 14c) was selected for further development as a result of these structure/activity studies.
A series of 3-(4-fluorophenyl)-1H-indoles substituted in the 1-position with 4-piperidinyl, 1,2,3,6-tetrahydro-4-pyridinyl, and 4-piperazinyl was synthesized. By variation of the substituents in the ...benzene part of the indole nucleus in 1-2-4-3-4-fluorophenyl)-1H-indol-1-yl-1-piperidinyl-ethyl-2- imidazolidinones, the highest 5-HT2 receptor affinity and selectivity with respect to dopamine D2 receptors and alpha 1 adrenoceptors were obtained by 5-methyl substitution. Different substituents were introduced in the 1-position of the piperidine ring in the 5-methyl-substituted derivative. Thus replacement of the 2-(2-imidazolidinon-1-yl)ethyl side chain with a 2-(1,3-dimethyl-1-ureido)ethyl or methyl substituent resulted in unchanged affinity and selectivity for 5-HT2 receptors. Replacement with a 2-3-(2-propyl)-2-imidazolidinon-1-ylethyl side chain reduced binding to alpha 1 adrenoceptors with a factor of four, while affinities for 5-HT2 and D2 receptors were retained, compared to the 3-unsubstituted imidazolidinone. Indoles substituted in the 1-position with 4-piperazinyl had generally weaker affinity for both 5-HT2 and D2 receptors compared to corresponding 4-piperidinyl- and 1,2,3,6-tetrahydro-4-pyridinyl-substituted indoles. Introduction of a methyl group in the 2-position of the 5-methyl-substituted indole resulted in further increase of selectivity for the 5-HT2 receptor. Compounds with potent receptor binding also potently inhibited the quipazine-induced head twitch syndrome in rats. The compounds were equally active after oral and subcutaneous administration and showed a long duration of action (> 24 h). In general, the derivatives were found to be considerably more potent at 24 h than at 2 h after the administration. The compounds within this series were prepared as analogues of the previously described 1-(4-fluorophenyl)-3-(4-piperidyl)-1H-indoles by interchange of the C-3 carbon atom and the nitrogen atom in the indole nucleus. The pharmacological results indicate that this isosteric replacement results in higher selectivity for 5-HT2 receptors compared to the former series. The 1-2-4-2,5-dimethyl-3-(4-fluorophenyl)-1H-indol-1-yl-1- piperidinylethyl-2-imidazolidinone has high affinity for 5-HT2 receptors (IC50 = 3.4 nM) and extremely low affinity for both dopamine D2 receptors (IC50 = 6900 nM) and alpha 1 adrenoceptors (IC50 = 2300 nM).
Circling behaviour induced by dopamine (DA) agonists with different D-1/D-2 receptor selectivity was studied in rats with hemitransection at a level caudal to the striatum. The mixed D-1/D-2 agonist ...apomorphine induced ipsilateral circling behaviour after administration of doses similar to those that induced stereotyped behaviour in unlesioned rats. The effect of apomorphine was not influenced by co-treatment with SK & F 38393 or quinpirole, indicating that apomorphine induces a comparable D-1 and D-2 receptor stimulation in vivo also. Three selective D-1 agonists, SK & F 38393, SK & F 75670 and Lu 24-040 had no effects alone, while the preferential D-2 agonists quinpirole, pergolide and (-)-N-propylnorapomorphine induced ipsilateral circling of weaker intensity than did apomorphine. After co-treatment with SK & F 38393 the effects of these compounds were markedly increased. Combination of SK & F 38393, SK & F 75670 or Lu 24-040 with quinpirole induced circling with intensities similar to those seen after apomorphine. Pretreatment with the D-1 antagonist SCH 23390 or the D-2 antagonist YM 09151-2 completely antagonized the ipsilateral circling induced by either apomorphine or quinpirole + SK & F 38393. A range of partial (autoreceptor) D-2 agonists, i.e. (-)-3-PPP, (+)-3-phenethyl-PP, terguride, EMD 23448 and B-HT 920 were all ineffective as was the alpha 2-adrenoceptor agonist clonidine. However, B-HT 920 induced strong ipsilateral circling after combination with SK & F 38393, whereas (-)-3-PPP was ineffective.
